ETHICAL ISSUES IN CLINICAL RESEARCH

1. ETHICAL ISSUES INCLINICAL RESEARCH Peter Wagner, M.D. Dept of Medicine, UCSD President, American Thoracic Society

2. A DISCUSSION SPARKED BY: ATS Conference on the ethical conduct of research in critically ill patients November 21-22, 2003 Challenge to the low tidal volume trial in ARDS (ARDSnet)

3. THERE MUST BE A CLEAR NEED FOR RESEARCH Unnecessary research is unethical Need is based on: 1. Persisting high mortality/morbidity 2. Limited understanding of disease 3. Limited specific therapeutics 4. Limited ability to predict outcome

4. RESEARCH MEANS ETHICAL ISSUES Ethical challenges are substantial from planning to publication Ethical integrity must be assured – Throughout the study

5. ETHICAL INTEGRITYTHROUGHOUT THE STUDY • When the research question is posed • As the study is designed • During subject identification • During the consent process • As the study is conducted • During data analysis • During dissemination of results

6. 1. When the research question is posed • There must be scientific validity • There must be social value • There must be independent review • Equipoise* should exist *Medical community genuinely uncertain about the value of the intervention

7. 2. As the study is designed • There must be scientific validity • The control arm must be chosen wisely • There must be justice (equitable risk • across subjects) • The risk:benefit ratio must be acceptable • The rules for stopping must be defined • Adverse event handling must be defined • Conflict of interest must be minimized

8. Control Groups • Proper design important to scientific validity • In mechanistic or efficacy trials, protocol driven control group isolates effect of intervention studied • In large effectiveness trials, control group should be within range of “best practice” • Consensus on best practice may be difficult • “Subject to certain conditions, there is justification for protocolizing care in the control arm … the investigator must attempt to insure the protocol is reflective of the best current practice.” Careful explanation of these distinctions is mandatory in informed consent.

9. 3. During subject identification • Selection to allow generalization (mostly) • Consideration for vulnerable groups • There must be justice (equitable • access across subjects) • The risk:benefit ratio must be acceptable • Obligation to avoid harm, provide benefit

10. 4. During the consent process • Who can/should/cannot give consent • Timing of obtaining consent • Who should seek consent • Person giving consent must be informed • Person giving consent must understand • Assure consent is truly voluntary • Assure the process follows the law

11. Waiver of Consent - 1996 1996 CFR Modification: Waiver of consent possible if : • Life threatening; available treatments unproven or unsatisfactory • Obtaining consent not feasible • Participation has prospect of direct benefit to subjects • Risks are reasonable relative to the medical condition of subjects • Research not possible without waiver • Investigator attempts to contact surrogate within prespecified time • Local IRB reviews and approves • Prior consult with representatives of communities involved in study

12. 5. As the study is conducted • Patient safety (DSMB) • Patient respect, privacy • Oversight for stopping (DSMB) • Investigator conflicts of interest • Best experimental methods, records • Conflict between caregiving and research • Staying within IRB approved limits

13. 6. During data analysis • Integrity during data processing • Patient privacy during data processing • Avoiding unnecessary delay in analysis • Appropriate sharing of data • Maintaining security of data

14. 7. During dissemination of results • Integrity in reporting • Patient respect, privacy • Avoiding unnecessary delay in reporting • Appropriate involvement by all involved • Consider sharing results with subjects

15. Major Recommendations • Separate research & practice for study participants • 3rd party consent if research & clinical care are mixed • Clinicians satisfied with study to have pts participate • Incorporate ethical checklists • Need laws recognizing surrogate consent for research • Revisit consent decisions during study • Share results of study with participants • Participant informed of possible individual benefit • Need to improve regulatory effectiveness & efficiency • Standardize DSMB • Better identify & manage conflict of interest

16. Ethical Checklist for Clinical Research Design • Will study results matter? • Is the study design scientifically valid? • Has design undergone independent review? • Appropriate participant selection? • Is risk:benefit ratio favorable? • Appropriate informed consent? • Procedures to insure respect for participants? • Are data and safety monitoring in place? • Conflicts of interest identified & minimized?

17. Sources of Conflict of Interest • Consultancies • Stock ownership • Patent rights • Industry funding • Competition for funding • Professional status or jealousies • Publish or perish rule • Personal curiosity

18. CONCLUSIONS • Major need for research must exist • Ethical challenges abound • At every stage from planning to reporting • These challenges must be faced • Perhaps most difficult are: • The issue of informed consent • When researcher and caregiver are one • Other conflicts of interest • Selecting the control treatment